PROJECT SUMMARY/ABSTRACT Alzheimer disease (AD) and related tauopathies are major diagnostic, therapeutic, and clinical challenges. The correlation between the clinical and neuropathological phenotypes of each tauopathy is not always clear: patients may appear to have one syndrome antemortem, while postmortem neuropathology indicates another. Moreover, the coincidence of multiple types of protein pathology (especially ?-synuclein and TDP-43) is the rule rather than the exception. This has critical implications for the classification of patients for treatment and could complicate selection of effective therapies, especially genetic or vaccine-based therapies. Our previous work suggest that prion mechanisms may govern progression of disease, whereby aggregates move from a sick cell to a healthy one, acting as templates for their own replication. This is supported by the finding that ?seeding activity? precedes frank neuropathology in human cases. Our work also indicates that unique, self-replicating tau aggregate conformations, or ?strains,? are linked to distinct tauopathies, and create unique, transmissible pathologies in animal models. These findings indicate prion mechanisms may underlie tauopathy, which may also be influenced by multiple amyloid-forming proteins. There is an urgent need to achieve accurate antemortem diagnosis, but this must be based on a clear elucidation of underlying pathology. We will use advanced seed and strain detection methods in human autopsy cases by: 1) testing whether tau seeding activity predicts and precedes classical neuropathological tau lesions; 2) using advanced methods to strain-type patients with distinct tauopathies; 3) developing more sensitive and specific methods to detect tau seeds and strains. We will utilize standard histopathology to track co-occurrence of other proteinopathies, and ?biosensor? cells to determine tau aggregate ?seeding activity? and strain identity brain tissues from patients diagnosed with AD and other tauopathies. We will correlate the composition and anatomic distribution of these findings with clinical phenotypes. We predict that tau seeding activity will correlate with brain regions involved or at risk for involvement from particular tauopathies, and, further, that tau strain identity will correlate with antemortem presentations of patients. Linking tau conformation with neuropathological phenotype and clinical presentation will greatly advance our understanding of disease mechanisms and will help us develop more specific diagnostics and therapies tailored to specific mechanisms of neurodegeneration.